Field of the Invention
The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 1-[Diisopropyl-phosphinoyl]-alkanes as described herein (DIPA-1-7, DIPA-1-8, and DIPA-1-9,) and certain 1-[Di-sec-butyl-phosphinoyl]-alkanes (2-6 and 2-7) that are useful in the treatment of disorders (e.g., diseases) and sensory discomfort (e.g., caused by inflammation, irritation, itch, or pain) originating from the nasal cavity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of swabs for topical delivery of such compounds and compositions to the nasal membranes, in particular to the region of the nasal membranes known as Kiesselbach's area.
Description of Related Art
Chemical sensory/cooling agents are molecules that can mimic the sensations of heat abstraction without a change in tissue temperatures. The exact sensations produced by chemicals depend on the selection of the active ingredient and the site and method of delivery. The term “chemical cooling agent” can be ambiguous because, for example, chemicals such as ethyl chloride as a gas, ethanol as a liquid, liquid nitrogen, or carbon dioxide as a solid, applied to the skin can evoke heat abstraction sensations by reducing tissue temperatures. In this application, chemical cooling agents will refer only to agents that elicit sensations of heat abstraction without a lowering of tissue temperatures.
Nasal stuffiness and congestion, and a sense of loss of patency and obstructed airflow, have many causes, the most common being “rhinitis”, a technical term meaning the condition of inflammation of the membranes lining the nose. Rhinitis is characterized by nasal congestion, rhinorrhea (“runny nose”), sneezing, itching of the nose and/or postnasal drainage. A common form of rhinitis is seasonal allergic rhinitis which is caused by seasonal aeroallergens such as pollens and molds [Seidman, M. D. et al. Clinical Practice Guideline: Allergic Rhinitis. Otolaryngol. Head Neck Surg. 152, S1-S43 (2015)]. Perennial allergic rhinitis is caused by perennial environmental aeroallergens such as dust mites, molds, animal allergens, or occupational allergens. Rhinitis can also be caused by food allergies. Some individuals, without evidence of allergic sensitization, will have rhinitis in reaction to nonspecific irritant stimuli such as cold dry air, perfumes, paint fumes, and cigarette smoke. This condition is called vasomotor rhinitis. Severe rhinitis may result from injury to the nasal membranes such as occurs after smoke inhalation, sinusitis, or after nasal surgery.
Rhinitis is also caused by the common cold virus. Initially, viral rhinitis is characterized by clear, watery rhinorrhea that is accompanied by sneezing and nasal obstruction. Edema of the nasal mucosa produces occlusion of the sinus ostia, with resulting facial pain, or of the Eustachian tube, with resulting ear fullness. Responsible viruses include rhinoviruses, respiratory syncytial virus, parainfluenza, influenza and adenoviruses. Fever may accompany viral rhinitis, especially if there is bacterial superinfection by streptococcal organisms.
The sinuses drain into the nasal cavity. Rhinosinusitis is inflammation of the mucosa of the nasal sinuses together with the nasal membranes. This condition is a major cause of breathing discomfort because it is accompanied by prolonged mucopurulent nasal discharge, facial pain and pressure, olfactory disturbance, and post-nasal drainage with cough.
Rhinitis is a common symptom. The prevalence of allergic rhinitis is estimated to be up to 20% of the general population. Individuals in the USA are estimated to have one or two bouts of the common cold per year. The economic burdens of rhinitis associated with allocation of health resources, from loss of work days, and from absence at schools are significant [Stewart, M. et al. Epidemiology and burden of nasal congestion. Int. J. Gen. Med. 3, 37-45 (2010)].
Pharmacological management of allergic rhinitis is a well-developed science. Effective medications for allergic rhinitis are the intra-nasally administered glucocorticosteroids [INS], intranasal antihistamines, and orally administered antihistamines. Sprays are used for topical treatments of the nasal membranes to deliver the active ingredients using manual pump-operated metered atomizers (e.g. Flonase®, Rhinocort®, Nasonex® and Nasocort®). The INS and antihistamines reduce nasal membrane inflammation and the symptoms and signs of allergic rhinitis. These compounds, in their current formulations have some side-effects such as nosebleeds [epistaxis], headaches, and pharyngitis for INS and bitter tastes for the intranasal antihistamines. Intranasal steroids are not effective for relieving the discomforts of infectious [e.g. viral] rhinitis, and have more limited efficacy for rhinosinusitis. INS and antihistamines are not less used for rhinitis caused by air pollutants wherein irritants directly damage the nasal mucosa.
Menthol, camphor and eucalyptus oil have been used since ancient times as remedies for nasal irritation and for refreshment of nasal sensations. These compounds may briefly provide cooling sensations in the nasal passages but are not effective for rhinitis. In fact these substances exacerbate nasal congestion and obstruction, especially in the late and delayed stages of rhinitis. In the laboratory, menthol is an irritant when instilled into the nasal passages of humans [Alenmyr, L. et al. TRPV1 and TRPA1 stimulation induces MUC5B secretion in the human nasal airway in vivo. Clin. Physiol. Funct. Imaging 31, 435-444 (2011)]. Menthol vapor delivered onto the membranes of the nasopharynx via orthograde or retrograde airflow [in the form of a menthol lozenge] has pungency and a cooling effect which briefly relieves nasal congestion. The pungency of menthol may stimulate vasoconstriction of the nasal blood vessels and this contributes to a brief decongestant action.
Other medications for nasal discomfort and rhinitis include sympathomimetic vasoconstrictors (decongestants) that reduce nasal blood flow and symptoms of congestion, but these compounds have a number of adverse side-effects, including rebound hyperemia (rhinitis medicamentosum). Zinc salts may shorten the duration of the common cold and thus reduce symptoms, but lozenges and syrups may have bad tastes and cause nausea [Singh, M. Zinc for the common cold (Review) Cochrane Library Database. (2014)]. There is a need for better medications to treat the signs and symptoms of nasal congestion and rhinitis.
It is a common experience that breathing cool air, for example at the seaside, will enhance the sense of fresh airflow in the nose. This effect has been demonstrated in the laboratory where subjects report a greater sense of nasal patency with lower nasal septum temperatures [Willatt et al. The role of the temperature of the nasal lining in the sensation of nasal patency. Clin. Otolaryngol. Allied Sci. 21, 519-523 (1996)]. Recently, it has been shown that peak mucosal heat loss in a critical region of the nose is a key correlate of the sense of nasal patency [Zhao, K. et al. Regional peak mucosal cooling predicts the perception of nasal patency. Laryngoscope 124, 589-595 (2014)]. This is a “Eureka!” event to me because it suggested that a strategy to mimic heat abstraction sensations in a localized anterior region of the nasal mucosa with a chemical agent may lead to a new method to treat the discomforts of nasal congestion.
Wei [AG-3-5: a chemical producing sensations of cold. J. Pharm. Pharmacol. 35: 110-112 (1983)]] discovered the cooling properties of icilin and gave this molecule its name. Wei [U.S. Pat. No. 6,933,301. Aug. 23, 2005] proposed that icilin administered into the nasal cavity may be useful for the relief of the symptoms of rhinitis, but this idea was not commercialized because of technical difficulties in formulating icilin for delivery into the nasal cavity.
Clarot and Hensley [U.S. Pat. No. 8,133,502] described the use of an applicator, enclosed in a sealed plastic container, for the delivery of a gelled composition to the nasal membranes. The active ingredient is selected from a group of moisturizer, a decongestant, or a homeopathic agent. Such enclosed swabs for nasal applications are now commercially available from Zicam [Nasal Swabs for Allergy Relief] and the listed active ingredients are Galphimia glauca, Histaminium hydrochloricum, Luffa operculata, and Sulfur. The label “Nasal Swabs with Cooling Menthol” is on the box of Zicam's swabs, but menthol is not listed under “Drug Facts” nor is the menthol content revealed.